The normal (emmetropic) eye has a refractive power and axial length which are balanced with each other. Seeing distant objects sharply occurs by the light rays passing through the eye's optical system in a passive way without any active muscular contraction. In the normal eye, only the focusing of near objects requires an active muscular increase in the refractive power of the eye. The hyperopic eye is either shorter or has a weaker refractive power and hence needs an active muscular mechanism to focus on distant objects (beyond about 6 meters) that has to be increased even further to focus on near objects. The myopic eye is either longer or has a too powerful refractive power, so distant objects appear blurry but near objects are in perfect focus without any active muscular intervention.
The active muscular mechanism of focusing of the human and primate eye involves the change in shape and position of the crystalline lens, produced by the contraction of the ciliary muscle of the eye that increases further the baseline refractive power of the eye. Starting in childhood, the crystalline lens begins to gradually lose its malleability and its capacity to change shape and position in response to the contraction of the ciliary muscle. From an optical standpoint, hyperopic eyes are generally affected first by this loss of malleability due to the need to increase the refractive power of the hyperopic eye to see clearly. Around age 40, the loss of malleability begins to affect normal eyes when they are unable to focus on near objects (40 centimeters or less from the eye) in a comfortable manner in a process called presbyopia.
In the eye, the ciliary muscle is under the control of the parasympathetic nervous system via acetylcholine and its muscarinic receptors. The sympathetic nervous system plays a secondary (regulatory) role via its alpha and beta receptors. Muscarinic agonists or stimulants increase the contraction of the ciliary muscle and hence increase the refractive power of the eye. From the sympathetic standpoint, alpha-2 and beta-2 stimulants produce the same contracting action on the ciliary muscle in part by allowing the parasympathetic system to work in an unopposed manner. If this stimulation is strong enough, some of the loss of the ability of the crystalline lens to change shape and position that normally occurs with age could be overcome while this stimulation is in place.
Another mechanism to be taken into account for treating presbyopia, is the effect on the dilating and sphincter muscles of the iris that change the diameter of the pupil. The iris sphincter is mainly under parasympathetic control via muscarinic receptors, although the sphincter does have some alpha and beta receptors. The iris dilating muscle is under sympathetic control, mainly alpha-1 and alpha-2 receptors with the alpha-1 stimulants producing dilation and the alpha-2 stimulants limiting dilation. The depth of the visual field of the eye could be increased by decreasing the diameter of the pupil. This is analogous to a photographic camera in which the depth of field increases as the diaphragm is closed. Hence the use of a muscarinic agonist (activating the iris sphincter) or an alpha-2 agonist (relaxing the dilating muscle of the iris) may constrict the pupil thereby increasing the depth of focus of the eye.
The most common way to correct presbyopia is by using reading glasses or bifocal glasses. There are also special contact lenses designed for this purpose. Several surgical treatments have also been devised for the treatment of presbyopia including special intraocular lenses, laser reshaping of the cornea, and scleral expansors. Exercises have been proposed as a way to delay the onset of presbyopia. However, the effectiveness of exercise in treating or preventing presbyopia has not been demonstrated in medical research. Pharmacological treatments for presbyopia have been proposed. However, many of these treatments have proven to be ineffective and/or have undesirable side effects.
Pilocarpine is an acetylcholine analog that acts as an agonist on the muscarinic receptors of the parasympathetic nervous system. It is a well-known antiglaucoma medication which has been in use as an ophthalmic preparation for more than 100 years. It is also used in an oral form to treat dry mouth/eyes. U.S. Pat. Nos. 6,291,466 and 6,410,544 describe one patient that had a decrease in his/her hyperopia of less than half a diopter after the application of 0.3% topical pilocarpine. A myopic patient had a decrease in his myopia after the same dose of pilocarpine which was counterintuitive.
U.S. Application No. 2010/0016395 A1 reports being able to increase the dose of pilocarpine to 1% to 2% by adding the non-steroidal anti-inflammatory agent diclofenac, but at a concentration that was five times more concentrated than that approved by the FDA. Congdon et al. reported that diclofenac is associated with serious side effects such as persistent epithelial defects, corneal melting, and corneal perforation. (Congdon et al., 2001, Corneal complications associated with topical ophthalmic use of nonsteroidal anti-inflammatory drugs, Ophthalmology, 27:622-631)
WO 2009/077736 discloses a combination of pilocarpine and dapiprazole (or thymoxamine) and pilocarpine and brimonidine (or iopidine) to treat defects of visual acuity, presbyopia, myopia, hypermetropia, low night vision, and astigmatism. The combinations listed are pilocarpine and dapiprazole (or thymoxamine), and pilocarpine and brimonidine (or iopidine). The combination of pilocarpine and dapiprazole produced red and irritated eyes (WO 2009/077736) and topical administration of brimonidine is known to those in the art to produce lightheadedness, dizziness, dry mouth, tachycardia, and stomach upset, among other side effects, which limits its usage even among patients using it for a severe eye condition such as glaucoma.
Although more than 75 molecules have been disclosed for the medical treatment of presbyopia, no clinically effective preparations suitable for use by the general public without unreasonable side effects have been found.